This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cone cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. This channel is composed of CNGA3 and CNGB3 subunits. Mutations in cone CNG channel are associated with achromatopsia, progressive cone dystrophy, and some maculopathies;with mutations in CNGB3 alone accounting for 50% of all known cases of achromatopsia. However, our understanding of this channel and related retinopathy is very limited. This is primarily due to the difficulty of investigating the cone system in a rod dominant mammalian retina. We proposed to study cone CNG channel under the normal and mutated conditions using mouse models. Our work shows that the cone dominant Nrl knockout mouse line is a useful model to study cone CNG channel. Using this mouse line we demonstrate that the native cone CNG channel is a heterotetrameric complex comprising both CNGA3 and CNGB3. By using CNGB3 knockout mice, we show the essential role of CNGB3 in cone function and survival. CNGB3 knockout mice show decreased cone function and develop cone degeneration. We also show that the CNGA3-Nrl double knockout mouse line is valuable to study the mechanism of cone degeneration. Using this mouse line we found a drastic accumulation of cGMP in the channel-deficient cones, implicating its role in cone death resulting from CNG channel deficiency. The long-term goal of our research is to elucidate the cellular and molecular mechanism(s) of cone defects in CNG channel deficiency with the objective of identifying potential therapeutic interventions for the cone diseases.